Acute hyperinsulinemia at euglycemia reduced circulating Fst by ~30% (p less then 0.001) and this response was intact in patients with T2D. Insulin inhibited FST expression in human hepatocytes after 2-hours and even further after 48-hours. CONCLUSIONS Elevated circulating Fst, but not activin A, is strongly associated with measures of insulin resistance in patients with T2D. However, the ability of insulin to suppress circulating Fst is preserved in T2D. © Endocrine Society 2020. All rights reserved. For permissions, please e-mail journals.permissions@oup.com.CONTEXT Recombinant human GH (rhGH) replacement therapy is often prescribed in patients with nonfunctioning pituitary adenoma (NFPA) or craniopharyngioma. OBJECTIVE To study whether rhGH therapy in patients with adult GH deficiency (AGHD) increases the risk of pituitary tumor recurrence. DESIGN Retrospective, observational study. SETTING Tertiary care center. PATIENTS We studied 283 consecutive patients with AGHD due to NFPA or craniopharyngioma between 1995 and 2018. INTERVENTION rhGH treatment at standard doses was initiated in 123 patients (43.5%). The remaining 160 patients served as controls. MAIN OUTCOME MEASURE Risk of tumor recurrence in rhGH-treated and control patients. https://www.selleckchem.com/Proteasome.html RESULTS In univariate analysis, recurrence of the pituitary tumor was less frequent in rhGH-treated patients (19.5%) than in controls (29.7%; HR 0.53, 95% CI, 0.32 - 0.86; p = 0.01). Multivariate Cox analysis demonstrated that the risk of tumor recurrence was associated with detection of residual disease at the baseline MRI (HR 9.17; 95% CI 4.88 - 17.22; p less then 0.001) and not having performed radiotherapy (HR 16.97; 95% CI 7.55 - 38.16; p less then 0.001), while rhGH treatment was no longer associated with a lower risk of recurrence (HR 0.82; CI 95% 0.47 - 1.44; p = 0.50). CONCLUSIONS we found no association between rhGH replacement and the risk of tumor recurrence in patients with AGHD caused by NFPA or craniopharyngioma. These data add to the mounting evidence that rhGH therapy has a neutral effect on the recurrence of pituitary tumors. © Endocrine Society 2020. All rights reserved. For permissions, please e-mail journals.permissions@oup.com.Biological and chemical DNA fragmentation generates DNA molecules with a variety of termini, including blunt ends and single-stranded overhangs. We have developed a Next Generation Sequencing (NGS) assay, XACTLY, to interrogate the termini of fragmented DNA, information traditionally lost in standard NGS library preparation methods. Here we describe the XACTLY method, showcase its sensitivity and specificity, and demonstrate its utility in in vitro experiments. The XACTLY assay is able to report relative abundances of all lengths and types (5' and 3') of single-stranded overhangs, if present, on each DNA fragment with an overall accuracy between 80-90%. In addition, XACTLY retains the sequence of each native DNA molecule after fragmentation and can capture the genomic landscape of cleavage events at single nucleotide resolution. The XACTLY assay can be applied as a novel research and discovery tool for fragmentation analyses and in cell-free DNA. © The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic Acids Research.BACKGROUND The demographic history of any population is imprinted in the genomes of the individuals that make up the population. One of the most popular and convenient representations of genetic information is the allele frequency spectrum (AFS), the distribution of allele frequencies in populations. The joint AFS is commonly used to reconstruct the demographic history of multiple populations, and several methods based on diffusion approximation (e.g., ∂a∂i) and ordinary differential equations (e.g., moments) have been developed and applied for demographic inference. These methods provide an opportunity to simulate AFS under a variety of researcher-specified demographic models and to estimate the best model and associated parameters using likelihood-based local optimizations. However, there are no known algorithms to perform global searches of demographic models with a given AFS. RESULTS Here, we introduce a new method that implements a global search using a genetic algorithm for the automatic and unsupervised inference of demographic history from joint AFS data. Our method is implemented in the software GADMA (Genetic Algorithm for Demographic Model Analysis, https//github.com/ctlab/GADMA). CONCLUSIONS We demonstrate the performance of GADMA by applying it to sequence data from humans and non-model organisms and show that it is able to automatically infer a demographic model close to or even better than the one that was previously obtained manually. Moreover, GADMA is able to infer multiple demographic models at different local optima close to the global one, providing a larger set of possible scenarios to further explore demographic history. © The Author(s) 2020. Published by Oxford University Press.MORC family CW-type zinc finger 2 (MORC2) is an oncogenic chromatin-remodeling enzyme with an emerging role in DNA repair. Here, we report a novel function for MORC2 in cell-cycle checkpoint control through an acetylation-dependent mechanism. MORC2 is acetylated by the acetyltransferase NAT10 at lysine 767 (K767Ac) and this process is counteracted by the deacetylase SIRT2 under unperturbed conditions. DNA-damaging chemotherapeutic agents and ionizing radiation stimulate MORC2 K767Ac through enhancing the interaction between MORC2 and NAT10. Notably, acetylated MORC2 binds to histone H3 phosphorylation at threonine 11 (H3T11P) and is essential for DNA damage-induced reduction of H3T11P and transcriptional repression of its downstream target genes CDK1 and Cyclin B1, thus contributing to DNA damage-induced G2 checkpoint activation. Chemical inhibition or depletion of NAT10 or expression of an acetylation-defective MORC2 (K767R) forces cells to pass through G2 checkpoint, resulting in hypersensitivity to DNA-damaging agents. Moreover, MORC2 acetylation levels are associated with elevated NAT10 expression in clinical breast tumor samples. Together, these findings uncover a previously unrecognized role for MORC2 in regulating DNA damage-induced G2 checkpoint through NAT10-mediated acetylation and provide a potential therapeutic strategy to sensitize breast cancer cells to DNA-damaging chemotherapy and radiotherapy by targeting NAT10. © The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic Acids Research.